Abstract
Epigenetic gene silencing by histone modifications and DNA methylation is essential for cancer development. The molecular mechanism that promotes selective epigenetic changes during tumorigenesis is not understood. We report here that the PIAS1 SUMO ligase is involved in the progression of breast tumorigenesis. Elevated PIAS1 expression was observed in breast tumor samples. PIAS1 knockdown in breast cancer cells reduced the subpopulation of tumor-initiating cells, and inhibited breast tumor growth in vivo. PIAS1 acts by delineating histone modifications and DNA methylation to silence the expression of a subset of clinically relevant genes, including breast cancer DNA methylation signature genes such as cyclin D2 and estrogen receptor, and breast tumor suppressor WNT5A. Our studies identify a novel epigenetic mechanism that regulates breast tumorigenesis through selective gene silencing.
Highlights
Both genetic and epigenetic alterations contribute to cancer development [1,2,3]
PIAS1 is important for breast tumorigenesis To directly test whether PIAS1 plays a functional role in breast tumorigenesis, RNA interference approach was used to knockdown the expression of PIAS1 protein in MDA-MB231 cells
When these cells were cultured under serum-free growth factorenriched conditions (Stem Cell Media; SCM), which favor normal stem cells and more closely resemble primary tumors than the DMEM condition [26], PIAS1 knockdown significantly inhibited the survival of MDA-MB231 cells (Fig. 1c, right panel)
Summary
Both genetic and epigenetic alterations contribute to cancer development [1,2,3]. Tumor suppressors and epigenetic gatekeeper genes are frequently silenced by epigenetic mechanisms during tumor initiation and progression [3,4,5]. More than 100 genes have been reported to be aberrantly hypermethylated in breast tumors or breast cancer cell lines [1,6]. Many of these genes play important roles in the regulation of cell cycle, apoptosis, angiogenesis, metastasis and tumor initiation. The approval of DNA methylation and histone deacetylase (HDAC) inhibitors for cancer treatment offers new promise for epigenetic therapy. These drugs are rather nonspecific, and the development of more effective strategies for epigenetic therapy requires a thorough understanding of the molecular specificity involved in epigenetic gene silencing
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
